# Patent

## Title
Mixtures or organic compounds for the treatment of airway diseases

## Abstract

A medicament comprising, separately or together, (A) a compound of formula (I) in free or pharmaceutically acceptable salt or solvate form and (B) a corticosteroid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease, the molar ratio of (A) to (B) being from 100:1 to 1:300.

## Background
This application is a continuation of U.S. application Ser. No. 10/433,546, filed Jun. 4, 2003 which is a national stage application of PCT Patent Application No. PCT/EP01/14122, filed Dec. 3, 2001 now U.S. Pat. No. 6,800,643, which are herein incorporated by reference.


This invention relates to organic compounds and their use as pharmaceuticals, in particular for the treatment of inflammatory or obstructive airways diseases.
In one aspect, the present invention provides a medicament comprising, separately or together, (A) a compound of formula 



in free or pharmaceutically acceptable salt or solvate form and (B) a corticosteroid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.

In another aspect, the present invention provides a method of treating an inflammatory or obstructive airways disease which comprises administering to a subject in need of such treatment effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined.
In a further aspect, the present invention provides a pharamceutical composition comprising a mixture of effective amounts of (A) as hereinbefore defined and (B) as hereinbefore defined, optionally together with at least one pharmaceutically acceptable carrier.
The invention further provides the use of (A) as hereinbefore defined and/or (B) as hereinbefore defined in the preparation of a medicament for combination therapy by simultaneous, sequential or separate administration of (A) and (B) in the treatment of an inflammatory or obstructive airways disease.
The compound of formula I may be prepared in free or salt or solvate form by reacting (R)-8-benzyloxy-5-oxiranylcarbostyril with 5,6-diethylindan-2-ylamine to give 8-benzyloxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-IH-quinolin-2-one, subjecting the latter to a deprotecting reaction to replace the benzyl group by hydrogen, and recovering the resultant compound of formula I in free or salt or solvate form. The reactions may be carried out using the procedures hereinafter described in the Examples or analogous procedures. (R)-8-benzyloxy-5-oxiranylcarbostyril may be prepared as described in WO95/25104. 5,6-Diethylindan-2-ylamine may be prepared by known methods or analogues thereof, for example as described hereinafter in the Examples.
Pharmaceutically acceptable salts of the compound of formula I may be acid addition salts, including those of inorganic acids, for example hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydriodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, p-chlorobenzoic acid, diphenylacetic acid, triphenylacetic acid, 1-hydroxynaphthalene-2-carboxylic acid, 3-hydroxynaphthalene-2-carboxylic acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as fumaric acid, maleic acid or succinc acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures. Pharmaceutically acceptable solvates are generally hydrates. A particularly preferred form of the compound of Formula I is the maleate salt.
The corticosteroid (B) may be, for example, of formula 



or a 1,2-dihydro derivative thereof, where

R1 is C1–C4-alkyl optionally substituted by halogen (preferably chlorine or fluorine), hydroxy, C1–C4-alkoxy, acyloxy or by acylthio, or R1 is C1–C4-alkoxy or C1–C4-alkylthio optionally substituted by halogen, or R1 is 5- or 6-membered heterocyclylthio, either R2 is acyloxy and R3 is hydrogen or C1–C4-alkyl, or R2 and R3 together denote a group of formula 



where R4 is C1–C4-alkyl or C3–C6-cycloalkyl and R5 is hydrogen or C1–C4-alkyl, and X1 and X2 are each independently hydrogen, chlorine or fluorine.

C1–C4-alkyl as used herein may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
C1–C4-alkoxy as used herein may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
C1–C4-alkylthio as used herein may be methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio.
When R1 is acyloxy-substituted C1–C4-alkyl, the acyloxy group may be, for example, C1–C20- alkylcarbonyloxy, e.g. acetyloxy, n-propionyloxy, isopropionyloxy or hexadecanoyloxy, or C3–C6-cycloalkylcarbonyloxy, e.g. cyclohexylcarbonyloxy. When R1 is acylthio-substituted C1–C4-alkyl, the acylthio group may be, for example, C1–C4-alkylcarbonylthio, e.g. acetylthio or n-propionylthio. When R1 is 5- or 6-membered heterocyclylthio, the heterocyclyl group may be an O-heterocyclyl group, for example a furanonyl group.
When R2 is acyloxy, it may be, for example, C1–C4-alkylcarbonyloxy, e.g. acetyloxy, n-propionyloxy, or n-butyroyloxy, C3–C6-cycloalkylcarbonyloxy e.g. cyclopropylcarbonyloxy, or 5- or 6-membered heterocyclylcarbonyloxy e.g. furoyloxy.
When R3 is C1–C4-alkyl it may be in the alpha or beta conformation, more usually in the alpha conformation.
When R2 and R3 together denote a group of formula III, R4 as C3–C6-cycloalkyl may be, for example, cyclohexyl.
Corticosteroids of formula I and their 1,2-dihydro derivatives include beclamethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, ciclesonide, triamcinolone acetonide, flunisolide, rofleponide palmitate, butixocort propionate and icometasone enbutate. In particularly preferred emodiments of the invention, the corticosteroid (B) is budesonide, fluticasone propionate or mometasone furoate.
Administration of the medicament or pharmaceutical composition as hereinbefore described, i.e. with (A) and (B) in admixture or separate, is preferably by inhalation, i.e. (A) and (B) or the mixture thereof are in inhalable form. The inhalable form of the medicament i.e. of (A) and/or (B) may be, for example, an atomizable composition such as an aerosol comprising the active ingredient, i.e. (A) and (B) separately or in admixture, in solution or dispersion in a propellant, or a nebulizable composition comprising a solution or dispersion of the active ingredient in an aqueous, organic or aqueous/organic medium. For example, the inhalable form of the medicament may be an aerosol comprising a mixture of (A) and (B) in solution or dispersion in a propellant, or a combination of an aerosol containing (A) in solution or dispersion in a propellant with an aerosol containing (B) in solution or dispersion in a propellant. In another example, the inhalable form is a nebulizable composition comprising a dispersion of (A) and (B) in an aqueous, organic or aqueous/organic medium, or a combination of a dispersion of (A) in such a medium with a dispersion of (B) in such a medium.
An aerosol composition suitable for use as the inhalable form of the medicament may comprise the active ingredient in solution or dispersion in a propellant, which may be chosen from any of the propellants known in the art. Suitable such propellants include hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons, and halogen-substituted hydrocarbons, for example chlorine and/or fluorine-substituted methanes, ethanes, propanes, butanes, cyclopropanes or cyclobutanes, such as dichlorodifluoromethane (CFC 12), trichlorofluoromethane (CFC11), 1,2-dichloro-1,1,2,2-tetrafluoroethane (CFC114) or, particularly, 1,1,1,2-tetrafluoroethane (HPA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227), or mixtures of two or more such halogen-substituted hydrocarbons. Where the active ingredient is present in suspension in the propellant, i.e. where it is present in particulate form dispersed in the propellant, the aerosol composition may also contain a lubricant and a surfactant, which may be chosen from those lubricants and surfactants known in the art. Other suitable aerosol compositions include surfactant-free or substantially surfactant-free aerosol compositions. The aerosol composition may contain up to about 5% by weight, for example 0.0001 to 5%, 0.001 to 5%, 0.001 to 3%, 0.001 to 2%, 0.001 to 1%, 0.001 to 0.1%, or 0.001 to 0.01% by weight of the active ingredient, based on the weight of the propellant. Where present, the lubricant and surfactant may be in an amount up to 5% and 0.5% respectively by weight of the aerosol composition. The aerosol composition may also contain a co-solvent such as ethanol in an amount up to 30% by weight of the composition, particularly for administration from a pressurised metered dose inhalation device. The aerosol composition may further contain a bulking agent, for example a sugar such as lactose, sucrose, dextrose, mannitol or sorbitol, in an amount, for example, of up to 20%, usually 0.001 to 1%, by weight of the composition.
In another embodiment of the invention, the inhalable form is a dry powder, i.e. (A) and/or (B) are present in a dry powder comprising finely divided (A) and/or (B) optionally together with at least one particulate pharmaceutically acceptable carrier, which may be one or more materials known as pharmaceutically acceptable carriers, preferably chosen from materials known as carriers in dry powder inhalation compositions, for example saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, mannitol or sorbitol. An especially preferred carrier is lactose. The dry powder may be contained as unit doses in capsules of, for example, gelatin or plastic, or in blisters (e.g. of aluminium or plastic), for use in a dry powder inhalation device, which may be a single dose or multiple dose device, preferably in dosage units of (A) and/or (B) together with the carrier in amounts to bring the total weight of powder per capsule to from 5 mg to 50 mg. Alternatively, the dry powder may be contained in a reservoir in a multi-dose dry powder inhalation device adapted to deliver, for example, 3–25 mg of dry powder per actuation.
In the finely divided particulate form of the medicament, and in the aerosol composition where the active ingredient is present in particulate form, the active ingredient may have an average particle diameter of up to about 10 μm, for example 0.1 to 5 μm, preferably 1 to 5 μm. The particulate carrier, where present, generally has a maximum particle diameter up to 300 μm, preferably up to 212 μm, and conveniently has a mean particle diameter of 40 to 100 μm, e.g. 50 to 75 μm. The particle size of the active ingredient, and that of a particulate carrier where present in dry powder compositions, can be reduced to the desired level by conventional methods, for example by grinding in an airjet mill, ball mill or vibrator mill, sieving, microprecipitation, spray-drying, lyophilisation or controlled crystallisation from conventional solvents or from supercritical media.
The inhalable medicament may be administered using an inhalation device suitable for the inhalable form, such devices being well known in the art. Accordingly, the invention also provides a pharmaceutical product comprising a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described in association with one or more inhalation devices. In a further aspect, the invention provides an inhalation device, or a pack of two or more inhalation devices, containing a medicament or pharmaceutical composition as hereinbefore described in inhalable form as hereinbefore described.
Where the inhalable form of the active ingredient is an aerosol composition, the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, such as 10 to 100 μl, e.g. 25 to 50 μl, of the composition, i.e. a device known as a metered dose inhaler. Suitable such aerosol vials and procedures for containing within them aerosol compositions under pressure are well known to those skilled in the art of inhalation therapy. For example, an aerosol composition may be administered from a coated can, for example as described in EP-A-0642992. Where the inhalable form of the active ingredient is a nebulizable aqueous, organic or aqueous/organic dispersion, the inhalation device may be a known nebulizer, for example a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion; or a hand-held nebulizer, sometimes referred to as a soft mist or soft spray inhaler, for example an electronically controlled device such as an AERx (Aradigm, US) or Aerodose (Aerogen), or a mechanical device such as a RESPIMAT (Boehringer Ingelheim) nebulizer which allows much smaller nebulized volumes, e.g. 10 to 100 μl, than conventional nebulizers. Where the inhalable form of the active ingredient is the finely divided particulate form, the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dry powder comprising a dosage unit of (A) and/or (B) or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, 3–25 mg of dry powder comprising a dosage unit of (A) and/or (B) per actuation. Suitable such dry powder inhalation devices are well known. For example, a suitable device for delivery of dry powder inencapsulated form is that described in U.S. Pat. No. 3,991,761, while a suitable MDPI device is that described in WO97/20589.
The medicament of the invention is preferably a pharmaceutical composition comprising a mixture of (A) as hereinbefore defined and (B) as hereinbefore defined, preferably together with at least one pharmaceutically acceptable carrier as hereinbefore described.
The molar ratio of the compound (A) to the steroid (B) may be, in general, from 100:1 to 1:300, for example from 50:1 to 1:100 or from 20:1 to 1:50, preferably from 10:1 to 1:20, more preferably from 5:1 to 1:10, from 3:1 to 1:7 or from 2:1 to 1:2. The compound (A) and the steroid (B) may be administered separately in the same ratio.
A suitable daily dose of the compound (A), particularly as the maleate salt, for inhalation may be from 20 μg to 2000 μg, for example from 20 to 1500 μg, from 20 to 1000 μg, preferably from 50 to 800 μg, e.g. from 100 to 600 μg or from 100 to 500 μg. A suitable daily dose of steriod (B) for inhalation may be from 20 μg to 5000 μg, for example from 20 to 4000 μg, from 50 to 3000 μg, from 50 to 2000 μg, from 50 to 1000 μg, from 50 to 500 μg, from 50 to 400 μg, from 50 to 300 μg, from 50 to 200 μg or from 50 to 100 μg. Where (B) is budesonide, a suitable daily dose may be from 25 to 4800 μg, for example from 25 to 4000 μg, from 25 to 3200 μg, from 25 to 2400 μg, from 25 to 1600 μg, from 50 to 4800 μg, from 50 to 4000 μg, from 50 to 3200 μg, from 50 to 2400 μg, from 50 to 1600 μg, from 100 to 4000 μg, from 100 to 3200 μg, from 100 to 2400 μg, from 100 to 1600 μg, from 100 to 800 μg, from 100 to 400 μg, from 200 to 4000 μg, from 200 to 1600 μg, from 200 to 800 μg or from 200 to 400 μg, 100 to 1600 μg being preferred. Where (B) is mometasone furoate, a suitable daily dose may be from 50 μg to 2000 μg, for example from 100 to 200 μg, from 100 to 1600 μg, from 100 to 1000 μg or from 100 to 800 μg, preferably from 200 to 500 μg, for instance from 200 to 400 μg. Where (B) is fluticasone propionate, a suitable daily dose may be for inhalation may be from 25 to 2000 μg, for example from 25 to 1500 μg, from 25 to 1000 μg, from 25 to 500 μg, from 25 to 250 μg, from 50 to 1500 μg, from 50 to 1000 μg, from 50 to 500 μg, from 50 to 250 μg, from 100 to 1500 μg, from 100 to 1000 μg, from 100 to 500 μg, from 100 to 2500 μg, from 200 to 1500 μg, from 200 to 1000 μg or from 200 to 500 μg, 100 to 1000 μg being preferred.
A suitable unit dose of compound (A), particularly as the maleate salt, may be from 20 to 2000 μg, for example from 20 to 1500 μg, from 20 to 1000 μg, preferably from 50 to 800 μg, from 50 to 600 μg or from 50 to 500 μg. A suitable unit dose of budesonide may be from 25 to 2400 μg, for example from 50 to 2400 μg, from 50 to 2000 μg, from 50 to 1600 μg, from 50 to 800 μg, from 50 to 400 μg, from 50 to 200 μg, from 100 to 1600 μg, from 100 to 800 μg, from 100 to 400 μg, from 100 to 200 μg, from 200 to 1600 μg, from 200 to 800 μg or from 200 to 400 μg, 100 to 400 μg being preferred. A suitable unit dose of mometasone furoate for inhalation may be from 25 to 2000 μg, for example from 50 μg to 1500 μg, from 50 to 1000 μg, from 50 to 800 μg, from 50 to 400 μg, from 50 to 200 μg, from 50 to 100 μg, from 100 to 800 μg, from 100 to 400 μg or from 100 to 200 μg, 100 to 400 μg being preferred. A suitable unit dose of fluticasone propionate for inhalation may be from 25 to 1000 μg, for example from 25 to 500 μg, from 25 to 250 μg, from 25 to 200 μg, from 50 to 1000 μg, from 50 to 500 μg, from 50 to 250 μg, from 50 to 200 μg, from 100 to 1000 μg, from 100 to 500 μg, from 100 to 250 μg, from 100 to 200 μg, from 150 to 500 μg or from 150 to 250 μg, 100 to 500 μg being preferred. These unit doses may be administered once or twice daily in accordance with the daily doses mentioned hereinbefore. The precise unit and daily dose used will of course depend on the condition to be treated, the patient and the efficiency of the inhalation device.
In one preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is a dry powder in a capsule containing a unit dose of (A) and (B), for example for inhalation from a single capsule inhaler, the capsule suitably containing a unit dose of (A) e.g. as hereinbefore described, and a unit dose of (B), e.g. as hereinbefore described, together with a pharmaceutically acceptable carrier as hereinbefore described in an amount to bring the total weight of dry powder per capsule to between 5 mg and 50 mg, for example 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg.
In another preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is a dry powder for administration from a reservoir of a multi-dose dry powder inhaler adapted to deliver, for example, 3 mg to 25 mg of powder containing a unit dose of (A) and (B) per actuation, for example, where (A) is in the form of the maleate salt, a powder comprising, by weight, 20 to 2000 parts, for example 60 to 1000 parts, 100 to 500 parts, or 100 to 300 parts of (A); 25 to 800 parts, e.g. 25 to 500 parts, 50 to 400 parts, or 100 to 400 parts of (B); and 2000 to 25000 parts, e.g. 4000 to 15000 parts or 4000 to 10000 parts of a pharmaceutically acceptable carrier as hereinbefore described.
In a further preferred embodiment of the invention, the medicament of the invention is a pharmaceutical composition which is an aerosol comprising (A) and (B), e.g. in a ratio as hereinbefore described, in a propellant as hereinbefore described, optionally together with a surfactant and/or a bulking agent and/or a co-solvent such as ethanol as hereinbefore described, for administration from a metered dose inhaler adapted to deliver an amount of aerosol containing a unit dose of (A) and a unit dose of (B), or a known fraction of a unit dose of (A) and a known fraction of a unit dose of (B), per actuation. Thus if, for example, the inhaler delivers half of the unit doses of (A) and (B) per actuation, the unit doses can be administered by two actuations of the inhaler.
In accordance with the above, the invention also provides a pharmaceutical kit comprising (A) and (B) as hereinbefore defined in separate unit dosage forms, said forms being suitable for administration of (A) and (B) in effective amounts. Such a kit suitably further comprises one or more inhalation devices for administration of (A) and (B). For example, the kit may comprise one or more dry powder inhalation devices adapted to deliver dry powder from a capsule, together with capsules containing a dry powder comprising a dosage unit of (A) and capsules containing a dry powder comprising a dosage unit of (B). In another example, the kit may comprise a multidose dry powder inhalation device containing in the reservoir thereof a dry powder comprising (A) and a multidose dry powder inhalaiton device containing in the reservoir thereof a dry powder comprising (B). In a further example, the kit may comprise a metered dose inhaler containing an aerosol comprising comprising (A) in a propellant and a metered dose inhaler containing an aerosol comprising (B) in a propellant.
The medicaments of the invention are advantageous in the treatment of inflammatory or obstructive airways disease, exhibiting highly effective bronchodilatory and anti-inflammatory properties. For instance, it is possible using the combination therapy of the invention to reduce the dosages of corticosteroid required for a given therapeutic effect compared with those required using treatment with a corticosteroid alone, thereby minimising possibly undesirable side effects. In particular, these combinations, particularly where (A) and (B) are in the same composition, facilitate achievement of a high anti-inflammatory effect, such that the amount of corticosteroid needed for a given anti-inflammatory effect may be reduced when used in admixture with a compound of formula I, thereby reducing the risk of undesirable side effects from the repeated exposure to the steroid involved in the treatment of inflammatory or obstructive airways diseases. Furthermore, using the combinations of the invention, particularly using compositions containing (A) and (B), medicaments which have a rapid onset of action and a long duration of action may be prepared. Moreover, using such combination therapy, medicaments which result in a significant improvement in lung function may be prepared. In another aspect, using the combination therapy of the invention, medicaments which provide effective control of obstructive or inflammatory airways diseases, or a reduction in exacerbations of such diseases, may be prepared. In a further aspect, using compositions of the invention containing (A) and (B), medicaments which reduce or eliminate the need for treatment with short-acting rescue medicaments such as salbutamol or terbutaline, may be prepared; thus compositions of the invention containing (A) and (B) facilitate the treatment of an obstructive or inflammatory airways disease with a single medicament.
Treatment of inflammatory or obstructive airways diseases in accordance with the invention may be symptomatic or prophylactic treatment. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as “wheezy infants”, an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as “wheezy-infant syndrome”.)
Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to “morning dipping”. “Morning dipping” is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
Other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis and emphysema, bronchiectasis and exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tobacosis and byssinosis.
The invention is illustrated by the following Examples, in which parts are by weight unless stated otherwise. In the Examples, Compound A is the compound of formula I in the form of the maleate salt, Bud denotes budesonide, FP denotes fluticasone propionate, MF denotes mometasone furoate and OA denotes oleic acid (surfactant).


PREPARATION EXAMPLES
Preparation 1—3-chloro-1-(3,4-diethylphenyl)-1-propanone
1,2-Diethylbenzene (10.9 g, 74.6 mmol) and propionyl chloride (9.7 g, 74.6 mmol) are added dropwise to AlCl3 (22.3 g, 167.8 mmol) in nitromethane (75 mL) over 30 min. The reaction mixture is stirred at room temperature for 2 hours, after which 70 g of ice and 14 mL concentrated sulphuric acid are added. The aqueous phase is extracted with ether, and the combined organic phases extracted with 2N HCl and saturated aqueous NaCl. The organic phase is further treated with activated charcoal, magnesium sulphate, and filtered, and the solvent removed in vacuo.
1H-NMR (CDCl3) ppm: 7.8 (1H, s, Ar); 7.7 (1H, d, Ar); 7.2 (1H, d, Ar); 3.9 (2H, t, CH2); 3.4 (2H, t, CH2); 2.8 (4H, q, CH2CH3); 1.2 (6H, m, CH3).
Preparation 2—5,6-diethyl-indan-1-one
3-chloro-1-(3,4-diethylphenyl)-1-propanone (15.5 g) is dissolved in 66 ml concentrated sulphuric acid and heated to 90° C. for 4 hours. The reaction mixture is cooled, ice (70 g) is added, and the aqueous solution extracted twice with toluene. The organic layer is washed with sodium bicarbonate, saturated aqueous NaCl, and treated with activated charcoal and magnesium suphate. After filtration, the solvent is removed in vacuo. The product is purified by flash column chromatography (silica, hexane/ethylacetate 10:1), and further crystallised in hexane.
1H-NMR (CDCl3) ppm: 7.6 (1H, s, Ar); 7.3 (1H, d, Ar); 3.1 (2H, m, CH2); 2.7 (6H, m, CH2+CH2CH3); 1.2 (6H, m, CH3).
Preparation 3—5,6-Diethyl-indan-1,2-dione 2-oxime
5,6-diethyl-indan-1-one (5 g, 26 mmol) in methanol (75 mL) is brought to 40° C., n-butyl nitrite (3.0 g, 28.6 mmol) is added dropwise, followed by the addition of concentrated HCl (1.25 mL). After 1 hour, the reaction is brought to room temperature and the precipitated product filtered off, washed with ice-cold methanol and dried.
1H-NMR (d6-DMSO) ppm: 12.6 (1H, s, OH); 7.4 (1H, s, Ar); 7.3 (1H, d, Ar); 3.6 (2H, s, CH2); 2.6 (4H, m, CH2CH3); 1.1 (6H, m, CH3).
Preparation 4—5,6-Diethyl-indan-2-ylamine hydrochloride
5,6-Diethyl-indan-1,2-dione 2-oxime (4.5 g) is added to a mixture of acetic acid (150 mL), and concentrated sulphuric acid (4.5 mL). Pd/C 5% (1.5 g) is added, the reaction mixture degassed with nitrogen, and hydrogenated for 5 hours. The catalyst is then removed by filtration, the pH brought to pH 10 with 4M NaOH, and the solution extracted with chloroform. The organic phase is dried with magnesium sulphate, and the solvent removed in vacuo. The residue is redisolved in a minimum amount of ether, and HCl saturated ether added. The white precipitate is filtered and dried to yield the HCl salt of 5,6-diethyl-indan-2-ylamine.
1H-NMR (d6-DMSO) ppm: 8.7 (3H, bd s, NH3); 7.3 (2H, s, Ar); 4.2 (1H, bd s, CH); 3.5 (2H, dd, CH2); 3.3 (2H, dd, CH2); 2.8 (4H, q, CH2CH3); 1.4 (6H, t, CH3).
Preparation 5—8-benzyloxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one
A solution of (R)-8-benzyloxy-5-oxiranylcarbostyril (5.00 g) and 5,6-diethylindan-2-ylamine (3.87 g) in n-butanol is heated for 4 hours at 110° C. After cooling to room temperature toluene (100 ml) is added and the organic phase is washed with water (3×25 ml), loaded onto a silica gel chromatography column and eluted with toluene followed by a mixture of toluene:ethanol:ethyl acetate:conc. ammonia (45:10:45:2) to give the title compound.
Preparation 6—Compound A: 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one maleate
8-benzyloxy-5-[(R)2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one (360 mg) is dissolved in methanol (10 mL) and the compound is deprotected by adding a catalytic amount of 10% palladium on charcoal and placing the solution under an atmosphere of hydrogen. The reaction is shown to be complete by TLC after 4 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is taken up into isopropanol and a solution of maleic acid in isopropanol added. The title compound is obtained after recrystallisation from ethanol. TLC (silica, dichloromethane/methanol 10:1 Rf=0.05). ES+MS m/e 393 (MH+).
Examples 1–60
Gelatin capsules suitable for use in a capsule inhaler such as that described in U.S. Pat. No. 3,991,761 are prepared, each capsule containing a dry powder obtained by mixing Compound A and budesonide which have been ground to a mean particle diameter of 1 to 5 μm and lactose monohydrate having a particle diameter below 212 μm, the amounts being as shown in the table below:

















Compound A
Budesonide
Lactose



Example
(Parts)
(Parts)
(Parts)





















1
20
100
19880



2
40
100
19860



3
80
100
19820



4
100
100
19800



5
120
100
19780



6
140
100
19760



7
160
100
19740



8
180
100
19720



9
200
100
19700



10
220
100
19680



11
240
100
19660



12
300
100
19600



13
500
100
19400



14
1000
100
18900



15
2000
100
17900



16
20
100
24880



17
40
100
24860



18
80
100
24820



19
100
100
24800



20
120
100
24780



21
140
100
24760



22
160
100
24740



23
180
100
24720



24
200
100
24700



25
220
100
24680



26
240
100
24660



27
300
100
24600



28
500
100
24400



29
1000
100
23900



30
2000
100
22900



31
20
200
14780



32
40
200
14760



33
80
200
14720



34
100
200
14700



35
120
200
14680



36
140
200
14660



37
160
200
14640



38
180
200
14620



39
200
200
14600



40
220
200
14580



41
240
200
14560



42
300
200
14500



43
500
200
14300



44
1000
200
13800



45
2000
200
12800



46
20
200
24780



47
40
200
24760



48
80
200
24720



49
100
200
24700



50
120
200
24680



51
140
200
24660



52
160
200
24640



53
180
200
24620



54
200
200
24600



55
220
200
24580



56
240
200
24560



57
300
200
24500



58
500
200
24300



59
1000
200
23800



60
2000
200
22800










Examples 61–90
Examples 1–60 are repeated, but replacing the budesonide by mometasone furoate, and using amounts as shown in the following table:

















Compound A
MF
Lactose



Example
(Parts)
(Parts)
(Parts)





















61
20
100
24880



62
40
100
24860



63
80
100
24820



64
100
100
24800



65
120
100
24780



66
140
100
24760



67
160
100
24740



68
180
100
24720



69
200
100
24700



70
220
100
24680



71
240
100
24660



72
300
100
24600



73
500
100
24400



74
1000
100
23900



75
2000
100
22900



76
20
200
14780



77
40
200
14760



78
80
200
14720



79
100
200
14700



80
120
200
14680



81
140
200
14660



82
160
200
14640



83
180
200
14620



84
200
200
14600



85
220
200
14580



86
240
200
14560



87
300
200
14500



88
500
200
14300



89
1000
200
13800



90
2000
200
12800










Examples 91–135
A dry powder suitable for delivery from the reservoir of the multi-dose inhaler described in W097/20589 is prepared by mixing Compound A and fluticasone propionate which have been ground to a mean particle diameter of 1–5 μm and lactose monohydrate having a particle diameter below 212 μm, the amounts being as shown in the table below

















Compound A
FP
Lactose



Example
(Parts)
(Parts)
(Parts)





















91
20
100
4880



92
40
100
4860



93
80
100
4820



94
100
100
4800



95
120
100
4780



96
140
100
4760



97
160
100
4740



98
180
100
4720



99
200
100
4700



100
220
100
4680



101
240
100
4660



102
300
100
4600



103
500
100
4400



104
1000
100
3900



105
2000
100
2900



106
20
200
9780



107
40
200
9760



108
80
200
9720



109
100
200
9700



110
120
200
9680



111
140
200
9660



112
160
200
9640



113
180
200
9620



114
200
200
9600



115
220
200
9580



116
240
200
9560



117
300
200
9500



118
500
200
9300



119
1000
200
8800



120
2000
200
7800



121
20
250
14730



122
40
250
14710



123
80
250
14670



124
100
250
14650



125
120
250
14630



126
140
250
14610



127
160
250
14590



128
180
250
14570



129
200
250
14550



130
220
250
14530



131
240
250
14510



132
300
250
14450



133
500
250
14250



134
1000
250
13750



135
2000
250
12750










Examples 136–163
Aerosol formulations are prepared by dispensing micronised active ingredients and, if required, lactose as bulking agent into a vial, sealing the vial with a metering valve, injecting the premixed ethanol/propellant and optional surfactant into the vial through the valve and subjecting the vial to ultrasonic energy to disperse the solid particles. The components and amounts used are shown in the following tables:




















Cpd. A

HFA134a
HFA227

OA
Lactose


Ex.
(Parts)
MF (Parts)
(Parts)
(Parts)
Ethanol (Parts)
(Parts)
(Parts)





136
2
10
36500
60750
2500
—
70


137
4
10
3410
6340
230
0.3
—


138
8
10
97000
—
2500
—
90


139
10
10
30500
67000
2500
0.5
100


140
12
10
3150
6550
250
1
—


141
14
10
3700
6050
250
0.8
—


142
16
10
3800
5900
230
0.4
—


143
18
10
4700
5050
250
1
—


144
20
20
3600
6150
225
1
—


145
22
20
3500
6200
230
1
—


146
24
20
98000
—
2500
1
—


147
30
20
3900
5900
250
1
—


148
2
20
30000
67000
2250
0.2
90


149
10
20
3500
6200
250
0.5
—


150
14
20
3200
6500
230
1
—


151
18
20
3100
6200
225
0.8
—


152
20
20
3150
6100
225
1
—


153
24
20
30000
60000
2000
0.8
—






Cpd. A

HFA134a
HFA227

OA
Lactose


Ex.
(Parts)
FP (Parts)
(Parts)
(Parts)
Ethanol (Parts)
(Parts)
(Parts)





154
4
10
34000
63000
2250
0.3
50


155
8
10
92000
—
2500
0.5
70


156
12
10
3000
5500
200
—
—


157
16
10
2500
5000
200
0.3
—


158
20
10
2000
3000
150
0.2
—


159
30
10
2000
2000
150
0.2
—


160
8
20
20000
25000
1500
0.2
—


161
12
20
2500
2500
200
0.2
—


162
20
20
2000
2000
150
0.2
—


163
30
20
20000
20000
1500
0.2
—









Examples 164–199
The procedure of Examples 91–135 is repeated, but replacing fluticasone propionate by mometasone furoate, and using amounts as shown in the following table.

















Compound A
MF
Lactose



Example
(Parts)
(Parts)
(Parts)





















164
100
100
4800



165
200
100
4700



166
300
100
4600



167
400
100
4500



168
500
100
4400



169
600
100
4300



170
700
100
4200



171
800
100
4100



172
2000
100
2900



173
100
200
4700



174
200
200
4600



175
300
200
4500



176
400
200
4400



177
500
200
4300



178
600
200
4200



179
700
200
4100



180
800
200
4000



181
1200
200
3600



182
100
400
4500



183
200
400
4400



184
300
400
4300



185
400
400
4200



186
500
400
4100



187
600
400
4000



188
700
400
3900



189
800
400
3800



190
100
100
9800



191
200
100
9700



192
300
100
9600



193
400
100
9500



194
500
100
9400



195
100
200
9700



196
200
200
9600



197
300
200
9500



198
400
200
9400



199
500
200
9300










Examples 200–236
The procedures of Examples 136–163 is repeated, but using the amounts shown in the following table, the ethanol being omitted in some of the Examples:




















Cpd. A

HFA134a
HFA227

OA
Lactose


Ex.
(Parts)
MF (Parts)
(Parts)
(Parts)
Ethanol (Parts)
(Parts)
(Parts)





200
20
20
5000
—
200
0.5
—


201
40
2
2500
2500
—
—
—


202
75
25
1500
3500
500
—
1


203
20
20
3600
6150
225
—
0.5


204
2
20
30000
67000
—
—
—


205
14
20
3200
6500
1500
—
4


206
20
20
3150
6100
1500
4
—


207
10
20
4700
5050
500
—
0.2


208
60
20
10000
10000
—
—
—


209
60
20
10000
10000
200
—
—


210
60
20
10000
10000
—
0.5
—


211
30
20
8000
12000
—
1
1


212
40
20
5000
15000
500
0.5
0.5


213
50
20
9000
11000
400
0.8
0.2


214
20
20
4600
5000
400
0.4
0.2


215
30
10
20000
25000
—
—
—


216
40
10
20000
30000
—
—
—


217
60
10
35000
65000
—
—
—






Cpd. A
FP
HFA134a
HFA227

OA
Lactose


Ex.
(Parts)
(Parts)
(Parts)
(Parts)
Ethanol (Parts)
(Parts)
(Parts)





218
20
10
5000
5000
—
—
1


219
10
10
3650
6350
—
—
1


220
30
10
3200
6800
100
0.5
0.5


221
30
20
7400
7600
100
—
—


222
40
20
8300
6700
200
0.5
—


223
60
20
3100
6900
300
1
—


224
10
10
8000
12000
—
—
—


225
50
20
1600
3400
500
2
0.5






Cpd. A
Bud
HFA134a
HFA227

OA
Lactose


Ex.
(Parts)
(Parts)
(Parts)
(Parts)
Ethanol (Parts)
(Parts)
(Parts)





226
10
20
5500
4500
—
—
—


227
2
20
3500
6500
—
—
1


228
1
20
2500
7500
—
—
1


229
20
20
3800
6100
100
0.5
—


230
15
20
3300
6600
100
0.5
0.5


231
30
20
3600
5900
500
4
—


232
40
20
4600
4900
500
3
—


233
30
10
3100
6800
100
0.2
0.5


234
40
10
1400
3100
500
0.2
—


235
60
10
8000
12000
—
—
1


236
80
10
30000
70000
—
—
—









Examples 237–245
The procedure of Examples 136–163 is repeated, but using sorbitan trioleate (ST) as surfactant in place of oleic acid, the amounts of the ingredients being as shown in the following table:


















Cpd. A

HFA134a
HFA227

ST
Lactose


Ex.
(Parts)
MF (Parts)
(Parts)
(Parts)
Ethanol (Parts)
(Parts)
(Parts)






















237
60
40
10000
10000
300
4
—


238
60
20
8000
12000
200
8
—


239
50
20
12000
8000
400
10
—


240
40
20
5000
5000
600
2.5
1


241
30
20
3500
6500
—
4
2


242
20
20
6000
4000
—
3
3


243
10
20
4500
5500
100
2
1


244
20
10
4100
5900
50
1
2


245
15
5
1550
3450
200
0.5
1

## Claims

1. A pharmaceutical composition comprising,
(a) a compound 



in free or pharmaceutically acceptable salt or solvate form; and
(b) a corticosteroid, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease, the molar ratio of (a) to (b) being from 100:1 to 1:300 and a pharmaceutically acceptable carrier.

2. A pharmaceutical composition according to claim 1, in which (a) is a compound of formula (I) in the form of the maleate salt.

3. A pharmaceutical composition according to claim 1, in which the corticosteroid (b) is of formula (II) 



or a 1,2-dihydro derivative thereof, where
R1 is C1–C4-alkyl optionally substituted by halogen, hydroxy, C1–C4-alkoxy, acyloxy or by acylthio, or
R1 is C1–C4-alkoxy or C1–C4-alkylthio optionally substituted by halogen, or
R1 is 5- or 6-membered heterocyclylthio, either
R2 is acyloxy; and
R3 is hydrogen or C1–C4-alkyl, or
R2 and R3 together denote a group of formula (III) 



where
R4 is C1–C4-alkyl or C3–C6-cycloalkyl; and
R5 is hydrogen or C1–C4-alkyl; and
X1 and X2 are each independently hydrogen, chlorine or fluorine.

4. A pharmaceutical composition according to claim 1, in which the corticosteroid (b) is beclamethasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, ciclesonide, triamcinolone acetonide, flunisolide, rofleponide palmitate, butixocort propionate or icometasone enbutate.

5. A method of treating chronic obstructive pulmonary disease which comprises administering to a subject in need of such treatment effective amounts of a composition as defined in claim 1.

6. A method of treating asthma which comprises administering to a subject in need of such treatment an effective amount of a composition according to claim 1.